Protective effects of polyphenols against mitochondrial membrane permeabilization induced by HEWL protofibrils

A large body of evidence suggests that amyloid fibril formation is a complicated process that proceeds through the formation of misfolded species, followed by heterogeneous and transient intermediates of various sizes and morphologies, including oligomers and protofibrils, and finally fibrillization of these transient species into matures fibrils. According to the prevailing viewpoint, oligomeric and protofibrillar species, rather than fibrillar aggregates, have been identified as the main species that are neurotoxic. In regard to the mechanism of oligomers toxicity, it has been proposed that interaction between oligomeric intermediates and cell membrane is a major determinant of cytotoxicity. In line with this concept, compounds (including polyphenols) that interfere with aggregate species to bind lipid membranes may serve as therapeutic agents for the treatment of amyloid-associated disorders. In a recent study, we reported on protective effects of some naturally occurring polyphenols against mitochondrial membrane permeabilization induced by Hen Egg White Lysozyme (HEWL) protofibrils. Accordingly, in the present study we focused on studies involving interaction of HEWL protofibrils with mitochondria isolated from various tissue including rat brain, liver and heart. Membrane permeabilization was investigated by incubation of mitochondria with some polyphenols, including Resveratrol and Curcumin, followed by monitoring release of mitochondrial enzymes. Obtained results clearly demonstrate heterogeneity in mitochondrial enzyme release together with a higher protection in liver and heart in comparison with those isolated from brain. We suggest that heterogeneity in cellular membrane including mitochondria, the primary targets of toxic protofibrils, may provide important insights into mechanism of toxicity. However, additional studies are needed to elucidate the detailed mechanisms involved.